The affluence of the 1990's along with the exponential increase in food production particularly in Western and Asian economies has resulted in feed patters that lead to obesity. Obesity is defined as being excessively overweight. Excessive weight is generally characterized by excessive body fat because unused energy is stored in the adipose tissues as fat.
Obesity has associated with it, economic and social costs. Obese people, an increasing proportion of developed and developing societies, are regarded as having out of control feeding habits often associated with low self-esteem. Moreover, obese persons are more likely to have medical problems associated with or exacerbated by the excess body weight. Examples of medical conditions caused, exacerbated or triggered by excessive weight include bone fractures, pains in the knee joints, arthritis, increased risk of hypertension, atherosclerosis, stroke, diabetes, etc.
Melanin concentrating hormone (MCH) is a 19 amino acid neuropeptide produced in the lateral hypothalamic area and zona incerta. Although MCH-expressing neurons project to numerous regions of the brain. MCH is processed from a larger pre-prohormone that also includes a second peptide, NEI, and possibly a third, NGE (Nahon, Crit Rev in Neurobiology, 8:221-262, 1994). MCH mediates its effects through at least two G protein-coupled receptors, MCHR1 and MCHR2 (Saito et al. Nature 400: 265-269, 1999; Hill et al., J Biol Chem. 276: 20125-20129, 2001). Both receptors are expressed in regions of the brain consistent with MCH neuronal projection and known MCH physiologic function (Hervieu et al., Eur J Neuroscience 12: 1194-1216, 2000; Hill et al., J Biol. Chem. 276: 20125-20129, 2001; Sailer et al., Proc Nat Acad. Sci. 98: 7564-7569, 2001).
Extensive evidence exists to support the orexigenic activity of MCH. MCH mRNA is elevated in rodent models of obesity and in the fasted state (Qu et al., Nature 380: 243-247, 1996). Intra-cerebroventricularly administered MCH increases feeding and blocks the anorexic effect of α-melanocyte stimulating hormone (Ludwig et al., Am J Physiol 274: E627-E633, 1998). MCH knockout mice (MCH−/− mice) are lean, hypophagic and hypometabolic (Shimada et al., Nature 396: 670-674, 1998), while MCH over-expressing transgenic mice are obese and insulin resistant (Ludwig et al., J Clin Invest 107: 379-386, 2001). MCHR1−/− mice have recently been reported to be lean and hypermetabolic, indicating that the R1 isoform mediates at least some of the metabolic effects of MCH (Marsh et al., Proc Nat Acad Sci 99: 3240-3245, 2002).
In addition to its effects on feeding, MCH has been implicated in regulation of the hypothalamic-pituitary-adrenal axis through modulation of CRF and ACTH release (Bluet-Pajot et al., J Neuroendocrinol 7: 297-303, 1995). MCH may also play a role in the modulation of reproductive function (Murray et al., J Neuroendocrinol 12: 217-223, 2000) and memory (Monzon et al., Peptides 20: 1517-1519, 1999).
The current preferred treatment for obesity as well as Type II non-insulin dependent diabetes is diet and exercise with a view toward weight reduction and improved insulin sensitivity for diabetics. Patient compliance, however, is usually poor. The problem is compounded by the fact that there are currently only two medications approved for the treatment of obesity (sibutramine, or Meridia™ and orlistat, or Xenical™.
PCT application number WO 01/21577 (JP00/06375) filed Sep. 19, 2000, discloses compounds reportedly useful as antagonists of the MCH receptor. In particular the WO 01/21577 application claims a compound of formula A
wherein:Ar1 is a cyclic group that may have substituents;X is a spacer having a main chain of 1 to 6 atoms;Y is a bond or a spacer having a main chain of 1 to 6 atoms;Ar is a monocyclic aromatic ring which may be condensed with a 4 to 8 membered non-aromatic ring, and may have further substituents;R1 and R2 are independently hydrogen atom or a hydrocarbon group which may have substituents;R1 and R2 together with the adjacent nitrogen atom may form a nitrogen-containing hetero ring which may have substituent; R2 may form a spiro ring together with Ar; or R2, together with the adjacent nitrogen atom and Y, may form a nitrogen-containing hetero ring which may have substituents; or salts thereof.
PCT application number WO 01/82925, filed Apr. 26, 2001, also discloses compounds reportedly useful as antagonists of the MCH receptor. In particular the WO 01/82925 application claims a compound of formula B
wherein:Ar1 is an optionally substituted cyclic group;X and Y are independently a spacer having a C1-6 main chain;Ar is an optionally substituted fused polycyclic aromatic ring;R1 and R2 are independently hydrogen atom or an optionally substituted hydrocarbon group; or alternatively R1 and R2 together with the nitrogen atom adjacent thereto may form a nitrogenous heterocycle, or R2 together with the nitrogen atom adjacent thereto and Y may form an optionally substituted nitrogenous heterocycle, or R2 together with the nitrogen atom adjacent thereto, Y, and Ar may form a fused ring.
PCT application number WO 01/87834, filed May 15, 2001, also discloses compounds reportedly useful as antagonists of the MCH receptor. In particular the WO 01/87834 application claims a compound of formula C.
wherein;R represents hydrogen, halogen, or an optionally substituted cyclic group; X represents a bond or a spacer in which the main chain has one to ten atoms; Y represents a spacer in which the main chain has one to six atoms; ring A represents a benzene ring which may have other substituents; ring B represents a five- to nine-membered nitrogen containing nonaromatic heterocycle which may have other substituents; and R1 and R2 are the same or different and each represents hydrogen, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or R1 and R2 may form an optionally substituted nitrogenous heterocycle in cooperation with the adjacent nitrogen atom and R2 may form an optionally substituted nitrogenous heterocycle in cooperation with the adjacent nitrogen atom and Y.
DE2502588 describes a compound of the formula:
Wherein the variables are as defined therein.
PCT International publication WO 03/033476 A1 discloses a compound of the formula (Ia):
comprising a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof, wherein the variables are as described therein.
Current treatments targeted at obesity have side effects. Examples of such treatments include various over-the-counter appetite suppressants. These agents have not been proven effective for all patients and for sustainable periods of time. Similarly, the approved treatments, sibutramine (Meridia™) and orlistat (Xenical™) have been associated with side effects which may compromise compliance and may preclude long term use for sustained weight loss for certain patient populations.
Therefore, there is a need for new and/or improved therapeutically effective agents useful as antagonists of melanin concentrating hormone to better control the dietary habits, minimize the preponderance of obesity and treat, prevent and/or ameliorate the effects of obesity, including for example diabetes.